In recent years significant effort has been devoted to the development of multimodality imaging. Since each medical imaging modality has unique strengths and limitations, it is often through the compound use of multiple modalities that the complete assessment of a patient is achieved. Interest in the area of multimodality imaging has also been prompted by the realization that such techniques offer much more sophisticated characterization of the morphology and physiology of tissues and organs, and that confidence gained in the accurate correspondence or registration of different modalities greatly enhances their value (Barillot C, Lemoine D, Le Briquer L, et al. Eur J Radiol 1993; 17:22-27.). Consequently, this improved value of imaging will ultimately allow for advances in diagnosis and evaluation of disease, image-guided therapeutic interventions, and assessment of treatment outcomes. The recent integration of computed tomography (CT) and positron-emission tomography (PET) systems is a good example of the advantages of the multimodal approach (Townsend D W. Mol Imaging Biol 2004; 6:275-290; Townsend D W, Carney J P, Yap J T, et al. J Nucl Med 2004; 45 Suppl 1:4S-14S; Townsend D W, Beyer T. Br J Radiol 2002; 75 Spec No:S24-30). The CT-PET combination has revolutionized the utilization of PET and served to increase the specificity of PET-based assessment. In the context of radiation therapy, there is a need to merge CT and magnetic resonance (MR) imaging with CT employed for 3D volumetric dose calculation (Rosenman J G, Miller E P, Tracton G, et al. Int J Radiat Oncol Biol Phys 1998; 40:197-205.) and MR for accurate delineation of the target and normal structures as it provides exceptional soft tissue definition. For example, accurate delineation and targeting of the prostate gland in radiation therapy of prostate cancer necessitates parallel use of CT and MR imaging (Rasch C, Barillot I, Remeijer P, et al. Int J Radiat Oncol Biol Phys 1999; 43:57-66.). Furthermore, CT technology in the form of conventional and cone-beam systems is employed on a daily basis to guide the delivery of radiation therapy on treatment machines (Uematsu M, Sonderegger M, Shioda A, et al. Radiother Oncol 1999; 50: 337-339; Jaffray D A, Siewerdsen J H, Wong J W, et al. Int J Radiat Oncol Biol Phys 2002; 53:1337-1349.).
Clinical imaging in all modalities requires an adequate level of differential contrast relative to noise be achieved in order to identify the structures or phenomena under observation. Although imaging on CT and MR can be performed without the administration of signal modifying agents there are numerous instances in both disease diagnosis and treatment, in which procedures benefit from the improved contrast and dynamics that are added by the use of these agents (Krause W. Adv Drug Deliv Rev 1999; 37: 159-173; Saeed M, Wendland M F, Higgins C B. J Magn Reson Imaging 2000; 12:890-898).
To date, although a multitude of signal modifying agents are commercially available for single modality imaging, few attempts have been made to develop signal modifying agents that can be used across multiple imaging modalities (McDonald M A, Watkin B S, Watkin K L. Small Invest Radiol 2003; 38:305-310; Bloem J L, Wondergem J. Radiology 1989; 171:578-579; Gierda D S, Bae K T. Radiology 1999; 210: 829-834; Quinn A D, O'Hare N J, Wallis F J, et al. J Comput Assist Tomogr 1994; 18: 634-636; Pena C S, Kaufman J A, Geller S C, et al. J Comput Assist Tomogr 1999; 23:23-24.). The lack of development in this area is likely due to challenges presented by the fact that the distinct imaging modalities have different sensitivities for different signal modifying agents (Krause W. Adv Drug Deliv Rev 1999; 37: 159-173.). A simple approach for realizing a multimodal signal modifying agent for CT and MR has been to exploit commercially available extracellular gadolinium-based signal modifying agents for enhancement in both of these modalities. In this case, the properties of gadolinium that allow for use in both CT and MR include its relatively high atomic number and paramagnetic characteristics (McDonald M A, Watkin B S, Watkin K L. Small Invest Radiol 2003; 38: 305-310; Bloem J L, Wondergem J. Radiology 1989; 171:578-579; Gierda D S, Bae K T. Radiology 1999; 210: 829-834; Quinn A D, O'Hare N J, Wallis F J, et al. J Comput Assist Tomogr 1994; 18:634-636; Pena C S, Kaufman J A, Geller S C, et al. J Comput Assist Tomogr 1999; 23:23-24.). However, due to their low molecular weight, these agents only remain in the vascular system for a short period of time, exhibit rapid dynamic distribution changes in different organs and are excreted quickly. The use of these agents for cross-modality imaging would therefore require both multiple administrations and fast imaging sequences. Also, the low gadolinium payload per molecule, relative to conventional iodinated signal modifying agents, would necessitate the administration of higher doses for adequate CT enhancement which may have implications in terms of both cost and toxicity (McDonald M A, Watkin B S, Watkin K L. Small Invest Radiol 2003; 38:305-310; Bloem J L, Wondergem J. Radiology 1989; 171:578-579; Gierda D S, Bae K T. Radiology 1999; 210:829-834; Quinn A D, O'Hare N J, Wallis F J, et al. J Comput Assist Tomogr 1994; 18:634-636; Pena C S, Kaufman J A, Geller S C, et al. J Comput Assist Tomogr 1999; 23:23-24.). Furthermore, the short in vivo residence time of these agents would impose limitations on the size of the anatomic region that could be imaged optimally and would exclude them from being used in image-guidance applications due to their inability to provide prolonged contrast enhancement for the entire course of treatment (Saeed M, Wendland M F, Higgins C B. J Magn Reson Imaging 2000; 12:890-898).
A viable way to effectively deliver the required amount of contrast in each imaging modality and to prolong the presence of the agents in vivo is to employ carriers such as liposomes. Specifically, liposome-based systems have been evaluated for either encapsulating (Kao C Y, Hoffman E A, Beck K C, et al. Acad Radiol 2003; 10:475-483; Leike J U, Sachse A, Rupp K. Invest Radiol 2001; 36:303-308; Leander P, Hoglund P, Borseth A, et al. Eur Radiol 2001; 11:698-704; Schmiedl U P, Krause W, Leike J, et al. Acad Radiol 1999; 6:164-169; Spinazzi A, Ceriati S, Pianezzola P, et al. Invest Radiol 2000; 35:1-7; Petersein J, Franke B, Fouillet X, et al. Invest Radiol 1999; 34:401-409; Leander P, Hoglund P, Kloster Y, et al. Acad Radiol 1998; 5 Suppl 1:S6-8; discussion S28-30; Krause W, Leike J, Schuhmann-Giampieri G, et al. Acad Radiol 1996; 3 Suppl 2:S235-237; Dick A, Adam G, Tacke J, et al. Invest Radiol 1996; 31:194-203; Revel D, Corot C, Carrillon Y, et al. Invest Radiol 1990; 25 Suppl 1:S95-97; Musu C, Felder E, Lamy B, et al. Invest Radiol 1988; 23 Suppl 1:S126-129; Zalutsky M R, Noska M A, Seltzer S E. Invest Radiol 1987; 22:141-147; Seltzer S E, Shulkin P M, Adams D F, et al. AJR Am J Roentgenol 1984; 143:575-579; Jendrasiak G L, Frey G D, Heim R C, Jr. Invest Radiol 1985; 20:995-1002; Torchilin V P. Curr Pharm Biotechnol 2000; 1:183-215; Schneider T, Sachse A, Robling G, Brandi M. Int J Pharm 1995; 117:1-12; Pauser S, Reszka R, Wagner S, et al. Anticancer Drug Des 1997; 12:125-135.) or chelating (Weissig V V, Babich J, Torchilin V V. Colloids Surf B Biointerfaces 2000; 18:293-299; Misselwitz B, Sachse A. Acta Radiol Suppl 1997; 412:51-55; Unger E, Needleman P, Cullis P, et al. Invest Radiol 1988; 23:928-932; Kabalka G, Buonocore E, Hubner K, et al. Radiology 1987; 163:255-258; Grant C W, Karlik S, Florio E. Magn Reson Med 1989; 11:236-243) single CT or MR signal modifying agents. Most of these liposome-based signal modifying agents have been explored for blood pool imaging due to the long in vivo circulation lifetimes that may be achieved for these carriers. Yet, liposomes have also been identified as suitable carriers for the delivery of agents to the lymphatic system since they have been shown to avoid aggregation at the site of injection and localize in lymph nodes (Nishioka Y, Yoshino H. Adv Drug Deliv Rev. 2001; 47:55-64; Moghimi S M, Rajabi-Siahboomi A R. Prog Biphys Molec Biol. 1996; 65:221-249; Oussoren C, Storm G. Adv Drug Deliv Rev 2001; 50:143-156). The potential use of liposome-based signal modifying agents for lymphatic imaging is worth noting as it is well-known that the lymph nodes are the primary site for the metastases of many cancers (Swartz M A. Adv Drug Deliv Rev. 2001; 50:3-20; Swartz M A, Skobe M. Microsc Res Tech 2001; 55:92-99.). Until recently, there were no available non-invasive methods for distinguishing between lymph nodes enlarged due to the presence of metastatic cancer cells and nodes enlarged due to inflammation, or for identifying cancerous nodes of normal size. With the advent of Combidex® (Advanced Magnetics, Inc. USA), lymph nodes can now be enhanced in MR, and metastatic nodes can be differentiated from normal or inflamed nodes based on morphology and changes in signal intensity between scans performed before and after signal modifying agent injection (Xiang Y, Wang J, Hussain S M, Krestin G P. Eur Radiol. 2001; 11:2319-2331). However no delivery system has been developed for prolonged co-localization in vivo of two or more signal modifying agent for multiple medical imaging.